Ensembl - Proto

License: Ensembl retrieves data from the Ensembl project, distributed under the EMBL-EBI Terms of Use. Attribution to the Ensembl project is required when the data is redistributed. The client wrapper code is Apache-2.0-licensed. Please refer to the data terms for full terms.

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Ensembl/ensembl-rest

Language agnostic RESTful data access to Ensembl data over HTTP

Sarah C. Dyer, Olanrewaju Austine-Orimoloye, … Vianey Paola Barrera-Enriquez

Nucleic Acids Research (2025)

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@article{dyer2025ensembl,
  title={{Ensembl} 2025},
  author={Dyer, Sarah C. and Austine-Orimoloye, Olanrewaju and Azov, Andrey G. and Barba, Matthieu and Barnes, If and Barrera-Enriquez, Vianey Paola and others},
  journal={Nucleic Acids Research},
  volume={53},
  number={D1},
  pages={D948--D957},
  year={2025},
  publisher={Oxford University Press},
  doi={10.1093/nar/gkae1071}
}

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proto-bio/proto-tools/proto_tools/tools/database_retrieval/ensembl

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Function	Description
`run_ensembl_lookup()`	Look up an Ensembl gene record by Ensembl gene ID or gene symbol	Docs Source
`run_ensembl_overlap()`	Fetch features overlapping an Ensembl region (default: gene; supports exon, regulatory, motif, va…	Docs Source
`run_ensembl_sequence()`	Fetch DNA / cDNA / CDS / protein sequence for an Ensembl ID	Docs Source
`run_ensembl_vep()`	Predict variant consequences from an HGVS notation via Ensembl’s Variant Effect Predictor REST en…	Docs Source
`run_ensembl_xrefs()`	Fetch cross-references from an Ensembl ID to external databases	Docs Source

Background

Ensembl (Dyer et al., 2025) is a genome annotation resource maintained by EMBL-EBI. It integrates gene and transcript models, the Ensembl Regulatory Build, cross-references to external databases, and variant consequence prediction with the Variant Effect Predictor (VEP) for human and other supported species. Coordinates returned by Ensembl are 1-indexed and inclusive, to match biological residue selection conventions. Each tool issues a single HTTP GET to the Ensembl REST API, whose base URL is https://rest.ensembl.org for the GRCh38 assembly. Setting assembly="GRCh37" routes requests to https://grch37.rest.ensembl.org instead. The endpoints used are /lookup/id/{id} and /lookup/symbol/{species}/{symbol} for ensembl-lookup, /sequence/id/{id} for ensembl-sequence, /overlap/id/{id} for ensembl-overlap, /xrefs/id/{id} for ensembl-xrefs, and /vep/{species}/hgvs/{hgvs} for ensembl-vep. Responses are parsed into typed Pydantic records, with the full upstream JSON preserved alongside in a raw_payload field. PascalCase keys such as Transcript, Exon, and Translation are kept verbatim so records round-trip cleanly. Results reflect the live Ensembl database at query time rather than a fixed release snapshot.

Learning Resources

Ensembl REST API documentation (Ensembl) - the live endpoint reference with request parameters, response shapes, and an interactive console.
Ensembl and the Ensembl REST API (EMBL-EBI Training) - guided courses on Ensembl data and programmatic access.

Tools

Ensembl Lookup (`ensembl-lookup`)

Retrieves a single gene record, either directly by Ensembl gene ID or by gene symbol scoped to a species, returning the typed EnsemblGene (identifier, symbol, biotype, genomic coordinates, canonical transcript) plus the source URL and raw payload. With expand enabled, the response includes the nested transcript, translation, and exon hierarchy.

API Reference

Source

Input: EnsemblLookupInput

ensembl_id

string

Ensembl gene ID (e.g. ENSG...).

symbol

string

Gene symbol (e.g. BRCA1).

Source

Config: EnsemblLookupConfig

species

enum

default:"homo_sapiens"

Species slug used when symbol is the input. Default homo_sapiens.Available options: homo_sapiens, mus_musculus, rattus_norvegicus, danio_rerio, saccharomyces_cerevisiae

assembly

enum

default:"GRCh38"

Genome assembly. GRCh38 (default) calls rest.ensembl.org; GRCh37 calls grch37.rest.ensembl.org.Available options: GRCh38, GRCh37

expand

boolean

default:"False"

Include transcripts, translations, and exons in the response. Default False matches Ensembl REST.

mane

boolean

default:"False"

Include MANE Select annotations (/lookup/id only; requires expand=True).

phenotypes

boolean

default:"False"

Include phenotype annotations on gene records (/lookup/id only).

utr

boolean

default:"False"

Include UTR coordinates per transcript (/lookup/id only; requires expand=True).

verbose

integer

default:"0"

Verbosity level (0=quiet, 1=info, 2=debug, 3=raw subprocess stderr). True is coerced to 1 and False to 0.

device

string

default:"cpu"

Device to run the tool on.

timeout

integer

default:"600"

Maximum execution time in seconds. None waits indefinitely.

seed

integer

Random seed. When set, tools run reproducibly up to small GPU float noise (see BaseToolOutput.approx_equal), and the seed participates in cache keys. When None, cacheable seed-sensitive tools skip cache until seeded.

Source

Output: EnsemblLookupOutput

result

EnsemblGene

required

The looked-up gene record.

Show EnsemblGene

string

required

Ensembl gene ID (ENSG…).

display_name

string

Human-readable gene symbol (e.g. ‘BRCA1’).

description

string

Free-text description.

biotype

string

required

Gene biotype (protein_coding, lncRNA, …).

species

string

required

Species slug (e.g. ‘homo_sapiens’).

seq_region_name

string

required

Chromosome / contig name.

start

integer

required

1-indexed inclusive genomic start.

end

integer

required

1-indexed inclusive genomic end.

strand

integer

required

+1 or -1.

assembly_name

string

required

Genome assembly name.

canonical_transcript

string

Canonical transcript ID with version.

Transcript

List[EnsemblTranscript]

Transcripts (PascalCase preserved from API); empty when expand=False.

source_url

string

required

Final Ensembl REST URL that was hit.

raw_payload

Dict[string, any]

Raw API JSON.

Applications

Use this to resolve a gene of interest as the entry point of nearly any Ensembl workflow. Convert a gene symbol such as BRCA1 into its stable Ensembl gene ID, read off the canonical transcript and genomic coordinates for downstream transcriptomics, GWAS annotation, or sequence retrieval with ensembl-sequence, or expand the transcript-and-exon hierarchy for splice-isoform analysis. The returned gene ID also feeds ensembl-overlap and ensembl-xrefs.

Usage Tips

Provide exactly one of ensembl_id or symbol. Supplying both or neither raises a validation error. A symbol lookup also requires config.species to disambiguate.
Nested transcripts and exons are absent unless expand is set. The default matches Ensembl REST and returns the gene record only, so request expansion explicitly when you need the transcript or exon hierarchy.
mane, phenotypes, and utr apply only to ID-based lookup. They are sent only on the /lookup/id path and are ignored for a symbol lookup. mane and utr additionally require expand.

Ensembl Sequence (`ensembl-sequence`)

Retrieves the sequence for an Ensembl gene, transcript, or protein ID and returns one or more EnsemblSequence records (stable ID, description, molecule type, sequence string) alongside the source URL and raw payload.

API Reference

Source

Input: EnsemblSequenceInput

ensembl_id

string

required

Ensembl ID (ENSG..., ENST..., or ENSP...).

Source

Config: EnsemblSequenceConfig

sequence_type

enum

default:"genomic"

What to return — genomic (DNA + UTRs + introns), cdna (spliced mRNA + UTRs), cds (spliced coding only), protein (translation).Available options: genomic, cdna, cds, protein

assembly

enum

default:"GRCh38"

Genome assembly. GRCh38 (default) or GRCh37.Available options: GRCh38, GRCh37

multiple_sequences

boolean

default:"False"

Return all sequences when an ID maps to multiple records (e.g. patches, alternative haplotypes).

mask

string

Mask repeats in the returned sequence. hard replaces with N; soft lowercases. Genomic sequence_type only; mutually exclusive with mask_feature.

mask_feature

boolean

default:"False"

Mask introns (when sequence_type='genomic') or UTRs (when sequence_type='cdna') so the primary feature stands out. Mutually exclusive with mask.

expand_3prime

integer

Bases to add to the 3’ end (genomic only, incompatible with end).

expand_5prime

integer

Bases to add to the 5’ end (genomic only, incompatible with start).

start

integer

1-indexed start trim coordinate (incompatible with expand_5prime).

end

integer

1-indexed end trim coordinate (incompatible with expand_3prime).

verbose

integer

default:"0"

Verbosity level (0=quiet, 1=info, 2=debug, 3=raw subprocess stderr). True is coerced to 1 and False to 0.

device

string

default:"cpu"

Device to run the tool on.

timeout

integer

default:"600"

Maximum execution time in seconds. None waits indefinitely.

seed

integer

Source

Output: EnsemblSequenceOutput

results

List[EnsemblSequence]

Fetched sequence record(s). Length 1 unless multiple_sequences=True and the ID maps to more than one.

Show EnsemblSequence

string

required

Stable ID echoed by the server. May differ from the input ID — for example, an ENST input with type=protein resolves to the corresponding ENSP.

desc

string

Description string returned by the server.

mol_type

string

Molecule type (‘dna’ / ‘protein’ / …).

seq

string

required

The raw sequence string.

molecule

string

Molecule type (‘dna’, ‘protein’, …)

source_url

string

required

Final Ensembl REST URL that was hit.

raw_payload

List[Dict[string, any]]

Raw API JSON, always wrapped in a list.

Applications

Use this to retrieve a reference sequence at gene, transcript, or protein granularity for any downstream analysis. Fetch the spliced mRNA or coding sequence of a canonical transcript resolved by ensembl-lookup for primer design, codon-usage analysis, or sequence comparison, pull the genomic span with introns for promoter or splice-site studies, or obtain the protein translation for multiple-sequence alignment or structure prediction. Repeat masking and feature masking support cis-element and intron-aware analyses.

Usage Tips

The returned id may differ from the input ID. Requesting a protein sequence for a transcript ID resolves to the corresponding protein ID, so read the record’s id rather than assuming it echoes the input.
mask and mask_feature are mutually exclusive, as are the expand and trim pairs. Setting both masks, or both expand_5prime and start, or both expand_3prime and end, raises a validation error.
Repeat masking and span expansion apply to genomic sequence only. They have no effect on cdna, cds, or protein requests.
Set multiple_sequences when an ID maps to more than one record. Without it, IDs that resolve to multiple sequences (patches, alternative haplotypes) return only the first.

Ensembl Overlap (`ensembl-overlap`)

Retrieves features overlapping the genomic region of a given Ensembl ID and returns a list of EnsemblOverlapFeatureRecord entries, each exposing the common typed fields (feature type, identifier, biotype, coordinates, strand, region) plus a raw dict carrying the full upstream record.

API Reference

Source

Input: EnsemblOverlapInput

ensembl_id

string

required

Ensembl ID whose region to query for overlapping features.

Source

Config: EnsemblOverlapConfig

overlap_feature

enum

default:"gene"

Type of feature to retrieve (e.g. gene, transcript, exon, regulatory, variation).Available options: band, gene, transcript, cds, exon, repeat, simple, misc, variation, somatic_variation, structural_variation, somatic_structural_variation, constrained, regulatory, motif, mane

assembly

enum

default:"GRCh38"

Genome assembly. GRCh38 (default) or GRCh37.Available options: GRCh38, GRCh37

biotype

string

Restrict to a biotype (e.g. protein_coding); most useful when overlap_feature is gene or transcript.

so_term

string

Restrict variation features by Sequence Ontology consequence (e.g. missense_variant).

variant_set

string

Restrict variation features to a named variant set (e.g. ClinVar).

verbose

integer

default:"0"

Verbosity level (0=quiet, 1=info, 2=debug, 3=raw subprocess stderr). True is coerced to 1 and False to 0.

device

string

default:"cpu"

Device to run the tool on.

timeout

integer

default:"600"

Maximum execution time in seconds. None waits indefinitely.

seed

integer

Source

Output: EnsemblOverlapOutput

result

List[EnsemblOverlapFeatureRecord]

Features overlapping the queried region; each carries the full upstream dict in raw for feature-specific keys.

Show EnsemblOverlapFeatureRecord

feature_type

string

required

Feature type (‘gene’, ‘transcript’, ‘exon’, ‘regulatory’, ‘motif’, ‘variation’, …).

string

Feature ID where the API returns one.

biotype

string

Biotype where applicable.

start

integer

required

1-indexed inclusive genomic start.

end

integer

required

1-indexed inclusive genomic end.

strand

integer

required

+1, -1, or 0 for unstranded features.

seq_region_name

string

required

Chromosome / contig name.

raw

Dict[string, any]

Full upstream record for feature-specific fields.

source_url

string

required

Final Ensembl REST URL that was hit.

raw_payload

List[Dict[string, any]]

Raw API JSON.

Applications

Use this to annotate a genomic locus by listing what overlaps it. Identify which gene or transcript contains a GWAS hit, ChIP-seq peak, or ATAC-seq peak, enumerate the regulatory-build features (promoters, enhancers, transcription-factor binding sites) within a region for functional-genomics analysis, or pull overlapping variants filtered to a named set such as ClinVar to ask whether the region is clinically annotated. The locus is typically obtained from ensembl-lookup.

Usage Tips

Records are typed only on the common fields. Feature-specific keys live in raw. Different feature classes return divergent payload shapes, so read per-feature attributes from each record’s raw dict.
biotype is most meaningful for gene and transcript features. It filters those classes. Pairing it with unrelated feature types is unlikely to narrow results.
so_term and variant_set apply to variation features. They have no effect when the feature class is not a variation type.

Ensembl Xrefs (`ensembl-xrefs`)

Resolves an Ensembl ID to its external-database cross-references and returns a list of EnsemblXref records (external database name, display and primary identifiers, description, cross-reference type) plus the source URL and raw payload.

API Reference

Source

Input: EnsemblXrefsInput

ensembl_id

string

required

Ensembl ID for direct cross-reference lookup.

Source

Config: EnsemblXrefsConfig

assembly

enum

default:"GRCh38"

Genome assembly. GRCh38 (default) or GRCh37.Available options: GRCh38, GRCh37

all_levels

boolean

default:"False"

Fan out to transcripts and translations. On a gene query this also returns xrefs from each child transcript and protein.

external_db

string

Restrict to one external database (e.g. UniProtKB/Swiss-Prot, HGNC).

object_type

string

Restrict to one feature type when the stable ID resolves ambiguously.

verbose

integer

default:"0"

Verbosity level (0=quiet, 1=info, 2=debug, 3=raw subprocess stderr). True is coerced to 1 and False to 0.

device

string

default:"cpu"

Device to run the tool on.

timeout

integer

default:"600"

Maximum execution time in seconds. None waits indefinitely.

seed

integer

Source

Output: EnsemblXrefsOutput

result

List[EnsemblXref]

Cross-reference records to external databases (UniProt, EntrezGene, RefSeq, …).

Show EnsemblXref

dbname

string

required

External database name (e.g. ‘Uniprot_gn’, ‘EntrezGene’).

db_display_name

string

Human-readable DB name.

display_id

string

required

Display identifier in the external DB.

primary_id

string

required

Primary identifier in the external DB.

description

string

External-DB description.

info_type

string

Cross-reference type (‘DIRECT’, ‘DEPENDENT’, …).

source_url

string

required

Final Ensembl REST URL that was hit.

raw_payload

List[Dict[string, any]]

Raw API JSON.

Applications

Use this to convert identifiers between Ensembl and the other major sequence, gene, and protein resources. Map an Ensembl gene or protein to a UniProt accession before fetching its entry with uniprot-fetch, which then bridges through to PDB structures via SIFTS, recover EntrezGene or RefSeq identifiers for NCBI-side retrieval, or follow GO and InterPro cross-references for functional annotation. The Ensembl ID is commonly produced by ensembl-lookup.

Usage Tips

Filter on dbname in the result, not just external_db. A single query can return several UniProt-related and RefSeq-related entries, so select the row by its dbname rather than assuming one record per database.
all_levels changes result scope on gene queries. It fans cross-references out to child transcripts and translations, which can substantially enlarge the result.
Set object_type when a stable ID resolves ambiguously. It restricts results to one feature type when the ID could map to a gene, transcript, or translation.

Ensembl VEP (`ensembl-vep`)

Submits an HGVS notation to the Ensembl Variant Effect Predictor REST endpoint and returns a list of EnsemblVEPConsequence records (echoed input, most severe consequence as a Sequence Ontology term, region and coordinates, allele string, raw per-transcript consequences, co-located variants) plus a derived num_consequences count.

API Reference

Source

Input: EnsemblVEPInput

hgvs

string

required

HGVS notation. Genomic (e.g. 9:g.22125504G>C), coding (ENST00000357654:c.5074G>A), or protein (ENSP00000418960:p.Tyr124Cys) forms all work.

Source

Config: EnsemblVEPConfig

species

enum

default:"homo_sapiens"

Species slug. Default homo_sapiens.Available options: homo_sapiens, mus_musculus, rattus_norvegicus, danio_rerio, saccharomyces_cerevisiae

assembly

enum

default:"GRCh38"

Genome assembly. GRCh38 (default) or GRCh37.Available options: GRCh38, GRCh37

annotations

EnsemblVEPAnnotationConfig

Collapsible group of species-agnostic annotation toggles.

Show EnsemblVEPAnnotationConfig

canonical

boolean

default:"False"

Mark canonical Ensembl transcripts in each consequence record.

hgvs

boolean

default:"False"

Include HGVS notation per consequence.

protein

boolean

default:"False"

Include Ensembl protein identifiers.

domains

boolean

default:"False"

List overlapping protein domain names.

numbers

boolean

default:"False"

Include affected exon/intron numbers.

variant_class

boolean

default:"False"

Include Sequence Ontology variant class.

uniprot

boolean

default:"False"

Include UniProt accession for each transcript.

xref_refseq

boolean

default:"False"

Include RefSeq cross-reference IDs.

mirna

boolean

default:"False"

Include overlapping miRNA target sites.

pubmed

boolean

default:"False"

Include PubMed citation IDs.

conservation

boolean

default:"False"

Include conservation scores from EPO alignments.

phenotypes

boolean

default:"False"

Include overlapping phenotype/disease annotations.

blosum62

boolean

default:"False"

Include BLOSUM62 substitution score for missense.

max_ent_scan

boolean

default:"False"

Include MaxEntScan splice-site scores.

verbose

integer

default:"0"

Verbosity level (0=quiet, 1=info, 2=debug, 3=raw subprocess stderr). True is coerced to 1 and False to 0.

device

string

default:"cpu"

Device to run the tool on.

timeout

integer

default:"600"

Maximum execution time in seconds. None waits indefinitely.

seed

integer

sift

string

SIFT pathogenicity output — b (both prediction + score), p (prediction only), s (score only); None falls back to API default.

polyphen

string

PolyPhen output level; same value semantics as sift.

mane

boolean

default:"False"

Include MANE Select annotations (GRCh38 only).

alphamissense

boolean

default:"False"

AlphaMissense missense pathogenicity scores (human only).

revel

boolean

default:"False"

REVEL ensemble pathogenicity scores (human only).

cadd

boolean

default:"False"

CADD deleteriousness scores (human only).

appris

boolean

default:"False"

Include APPRIS principal isoform tag (human/mouse only).

tsl

boolean

default:"False"

Include transcript support level (human/mouse only).

ccds

boolean

default:"False"

Include CCDS identifier per transcript (human/mouse only).

distance

integer

Up/downstream distance (bp) used to assign consequence terms. None keeps the API default (5000).

pick

boolean

default:"False"

Return only one consequence per variant — Ensembl’s PICK heuristic (canonical, longest CDS, …).

per_gene

boolean

default:"False"

Return one consequence per gene (less aggressive than pick); incompatible with pick.

verbose

integer

default:"0"

Verbosity level (0=quiet, 1=info, 2=debug, 3=raw subprocess stderr). True is coerced to 1 and False to 0.

device

string

default:"cpu"

Device to run the tool on.

timeout

integer

default:"600"

Maximum execution time in seconds. None waits indefinitely.

seed

integer

Source

Output: EnsemblVEPOutput

consequences

List[EnsemblVEPConsequence]

One record per VEP input (Ensembl returns a list even for a single HGVS).

Show EnsemblVEPConsequence

input

string

required

HGVS string the API echoed back.

most_severe_consequence

string

required

Highest-severity consequence term (Sequence Ontology: intron_variant, missense_variant, stop_gained, …).

seq_region_name

string

Chromosome / contig.

start

integer

1-indexed inclusive genomic start.

end

integer

1-indexed inclusive genomic end.

strand

integer

+1 or -1.

allele_string

string

Reference/alternate alleles (e.g. ‘G/C’).

transcript_consequences

List[Dict[string, any]]

Per-transcript consequence records — kept as raw dicts because the field set (sift_prediction, polyphen_prediction, codons, amino_acids, …) varies by consequence type and plugin configuration.

colocated_variants

List[Dict[string, any]]

Co-located known variants (rsIDs, frequencies, clinical significance) — also kept raw.

source_url

string

required

Final URL hit.

raw_payload

List[Dict[string, any]]

Raw API JSON.

Applications

Use this to predict the functional consequence of a variant and assess its likely impact. Classify a coding or genomic HGVS notation as missense, synonymous, stop-gain, splice-disrupting, or noncoding, then read per-transcript SIFT and PolyPhen predictions alongside optional human-only AlphaMissense, REVEL, and CADD pathogenicity scores for clinical or research variant interpretation. Co-located variant lookups surface population-frequency context from gnomAD and ClinVar annotations. Candidate variants are often identified from features returned by ensembl-overlap or from a designed or observed substitution in a downstream design workflow.

Usage Tips

transcript_consequences and colocated_variants are returned as raw dicts. Their field sets vary by consequence type and annotation toggles, so read them defensively rather than expecting a fixed shape.
pick and per_gene cannot be combined. Setting both raises a validation error. Choose one collapse strategy.
Several annotations are species- or assembly-restricted. MANE applies to GRCh38 only. AlphaMissense, REVEL, and CADD are human only. APPRIS, TSL, and CCDS are human and mouse only. Enabling a restricted annotation outside its scope simply yields no extra data.
A coding or genomic HGVS form is more reliable than a protein form. A protein-level notation can map to multiple transcripts ambiguously, so prefer coding or genomic notation when available.

Toolkit Notes

These apply to every Ensembl tool in this toolkit (ensembl-lookup, ensembl-sequence, ensembl-overlap, ensembl-xrefs, ensembl-vep).

Requires network access. Every tool calls the live Ensembl REST API. None runs offline and no local copy of the database is kept.
Subject to the Ensembl REST rate limit. Ensembl REST enforces a uniform per-IP limit of roughly 55,000 requests per hour, returning HTTP 429 with a Retry-After header when exceeded. There is no account or API key that raises this limit.

Example notebook: See the full working example for a copy-paste-ready walkthrough.

Infrastructure Guides

The following guides cover how to run tools efficiently and at scale.

Tool Persistence

Keep a tool’s model warm across calls instead of reloading it every invocation.

Device Management

How GPUs are allocated to tools and how to target specific devices.

Parallel Execution

Fan a batch of inputs out across multiple GPUs.

Cloud Inference

Run tools on managed cloud infrastructure with no local setup.

​Background

​Learning Resources

​Tools

​Ensembl Lookup (ensembl-lookup)

​API Reference

​Applications

​Usage Tips

​Ensembl Sequence (ensembl-sequence)

​API Reference

​Applications

​Usage Tips

​Ensembl Overlap (ensembl-overlap)

​API Reference

​Applications

​Usage Tips

​Ensembl Xrefs (ensembl-xrefs)

​API Reference

​Applications

​Usage Tips

​Ensembl VEP (ensembl-vep)

​API Reference

​Applications

​Usage Tips

​Toolkit Notes

​Infrastructure Guides

Tool Persistence

Device Management

Parallel Execution

Cloud Inference

Background

Learning Resources

Tools

Ensembl Lookup (`ensembl-lookup`)

API Reference

Applications

Usage Tips

Ensembl Sequence (`ensembl-sequence`)

API Reference

Applications

Usage Tips

Ensembl Overlap (`ensembl-overlap`)

API Reference

Applications

Usage Tips

Ensembl Xrefs (`ensembl-xrefs`)

API Reference

Applications

Usage Tips

Ensembl VEP (`ensembl-vep`)

API Reference

Applications

Usage Tips

Toolkit Notes

Infrastructure Guides